Abstract: We propose to transform pollen grains into a powerful and broadly applicable oral vaccination platform. Oral vaccine delivery has been a longstanding goal in the field of vaccination because it is needle-free, can be selfadministered and can produce both systemic and mucosal immune responses. Mucosal immunity is a powerful host-regulated defense at the mucosal surfaces that can neutralize pathogens while they are still outside the human body, before they can cause infection. The gastrointestinal mucosa like other mucosal surfaces suffers from constant onslaughts of microbes and forms a major portal of pathogen entry. Therefore, being able to stimulate mucosal immunity at the gastrointestinal mucosa will offer a tremendous immunological advantage to humans to help fight-off microbial invasions. The major roadblocks that continue to obstruct successful oral vaccination are the degradation of vaccines in the stomach and their poor uptake across the intestinal epithelial cell lining. Pollen grains are a natural engineering marvel with potential to address these roadblocks. Pollen grains have very tough exterior shells, which can withstand the acidic and enzymatic environment of the stomach and they can pass in to the body as intact particles across the tight epithelial cells of the gastrointestinal mucosa. We propose to exploit these fantastic natural particles and transform them into Trojan horses to safely ferry vaccine antigens across the harsh environment of the stomach and across the tight epithelial barrier, into the body. We have tested the feasibility of our seemingly peculiar idea by feeding mice with pollen grains filled with ovalbumin as a model antigen. Anti-ovalbumin immunoglobulin G (IgG) antibodies were produced in mouse serum after the vaccination. Importantly, the anti-ovalbumin IgG levels induced by pollen grains were found to be more than ten-fold higher than the anti-ovalbumin IgG levels induced by the use of cholera toxin (CT) as a positive control. This result is very significant because CT as a mucosal adjuvant is the current gold standard for oral vaccination and our data suggests that pollen grains are superior to CT. We are very excited by this discovery and we propose to further develop this promising strategy for oral vaccination through a multidisciplinary approach bridging the fundamentals of bioengineering, drug delivery and vaccinology. Our two complementary goals that will move this approach closer to human trials are: (i) characterize pollen grains and develop a mechanistic understanding of their Trojan ability, and (ii) understand mucosal and systemic immune responses generated by pollen grain-based oral vaccination and explore the potential of immunomodulation by the synergistic use of adjuvants. Overall, this pollen grain-based oral vaccine delivery platform is expected to be highly versatile and thus has potential to be harnessed for development of mucosal vaccines against a host of infectious diseases. Public Health Relevance: This project seeks to develop a novel methodology for oral vaccination, which is painless, child-friendly, safer and functionally superior to the exiting intramuscular route of vaccination using hypodermic needles. The delivery methodology will have broad applicability and will be able to deliver a broad range of vaccines.